title: Formulation of Docetaxel by folic acid-conjugated d-α-tocopheryl polyethylene glycol succinate 2000 (Vitamin E TPGS(2k)) micelles for targeted and synergistic chemotherapy.
abstract: Although high efficacy has been showed, Paclitaxel and Docetaxel cause serious side effects due to the adjuvant used in their clinical formulation Taxol® and Taxotere®. We developed a micelle system with a newly synthesized TPGS(2k) polymer, which shows lower CMC of 0.0219 mg/ml compared with 0.2 mg/ml for traditional micelles with TPGS involved, to achieve sustained and controlled drug delivery with Docetaxel used as a model anti-cancer drug. The TPGS(2k) micelles were further conjugated to folic acid (FA) for targeted drug delivery. The Docetaxel-loaded TPGS(2k) micelles with and without FA conjugation were found of desired size and size distribution, high drug encapsulation efficiency and favorable drug release. In vitro studies using MCF-7 cancer cells demonstrated significantly the higher cellular uptake of the formulated drug for TPGS(2k) micelle formulation than that for Taxotere®. The targeting effects for the FA conjugated TPGS(2k) micelles are also demonstrated. The IC₅₀ value, which is the drug concentration needed for 50% cell viability in the designated time period, is 103.4, 1.280 and 0.1480 μg/ml for MCF-7 cancer cells after 24, 48, and 72 h treatment respectively, which is greatly decreased to be 0.526, 0.251 and 0.233 μg/ml, i.e. a 99.5%, 80.4% decrease and 57.5% increase for the TPGS(2k) micelle formulation, and further decreased to be 0.1780, 0.1520 and 0.1140 μg/ml, i.e. a 99.8%, 88.1% and 23.0% decrease for the folic acid conjugated micelles, respectively. A synergistic effect between TPGS(2k) and Docetaxel is also achieved. The present work represents a new concept in the design of drug delivery systems--the carrier materials of the drug delivery system can also have therapeutic effects, which either modulate the side effects of, or promote a synergistic interaction with the formulated drug.
authors.affiliation: Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mi
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Si-Shen
authors.initials: SS
authors.lastname: Feng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008823:Micelles; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D036103:Nanotechnology; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D043823:Taxoids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D008823:Micelles; D011108:Polymers; D043823:Taxoids; D014810:Vitamin E; D000077143:Docetaxel; D011092:Polyethylene Glycols; D005492:Folic Acid; C014225:tocophersolan